There is evidence that obesity increases the risk of developing asthma, but the mechanistic basis for this link is unknown. Although changes in the mechanics of the respiratory system could explain this phenomenon, preliminary data suggest a novel hypothesis, that obesity promotes AHR through leptin induced augmentation of inflammation. The hormone leptin is released from adipocytes and has hypothalamic effects on eating and energy expenditure. Serum leptin correlates with adiposity and is increased in obese humans. Preliminary date indicate that in mice obese as a result of a genetic deficit in carboxypeptidase E (Cpefat mice) and which have high serum leptin, ozone (O3) induced airway inflammation is increased. However it appears that obesity per se does not promote AHR since O3-induced airway hyperresponsiveness (AHR) is reduced in mice that are genetically deficient in either leptin itself or the leptin receptor, even though the mice are markedly obese. To test this hypothesis, measurements of O3 and allergen-induced AHR and airway inflammation will be made in mice that are obese as a result of deficiencies in the leptin gene (ob/ob) or the leptin receptor (db/db), and mice that are obese but have high leptin levels (fat, tub and agouti mice and mice on high fat diets). In addition, exogenous leptin will be administered to control and ob/ob mice to acutely increase serum leptin, or control mice fasted overnight to acutely decrease serum leptin, and effects on AHR and airway inflammation examined. If pro-inflammatory effects of leptin contribute to obesity induced AHR, then O3 and allergen-induced AHR and inflammation should be enhanced in mice with high leptin levels and in mice that receive exogenous leptin, but reduced in ob/ob and db/db mice and in fasted mice. Understanding the mechanistic basis for the increased risk of asthma in obese subjects might lead to new public health strategies or therapeutic modalities for the treatment of asthma.